The following is a summary of “Genome-wide open reading frame profiling identifies fibroblast growth factor signaling as a driver of PD-L1 expression in head and neck squamous cell carcinoma,” published in the November 2023  issue of Oncology by Mann et al.

Head and neck squamous cell carcinomas (HNSCC) are linked to a lot of problems during treatment and a low chance of surviving both the disease and getting it again, especially in cases where the cancer has spread to other parts of the body. Stopping the programmed death-1/ligand-1 (PD-1/PD-L1), the immune block, is the best way to treat R/M HNSCC and is used in neoadjuvant, definitive, and adjuvant settings. To determine how cellular signals affect PD-L1 in HNSCC, the researchers looked at an HNSCC cell line with a genome-wide open reading frame (ORF) library with 17,000 different constructs or genes. 

Researchers found 335 ORFs that were more common in cells that had high levels of PD-L1. Five ORFs—FGF6, IL17A, CD300C, KLR1C, and NFKBIA—were separately confirmed to be the ones that raised PD-L1. They proved that an outside FGF ligand is enough to make several types of HNSCC cells, and human immature dendritic cells express PD-L1. Therefore, overexpression of FGFR1, FGFR3, or the FGFR3 S249C and D786N mutants common in HNSCC tumors led to overexpression of PD-L1 on tumor cells. Small molecules blocking FGF signaling stopped PD-L1 from upregulated in these models. 

They also stopped “classical” IFNγ-regulated PD-L1 expression in a way that did not depend on STAT1. Finally, they discovered that FGF specifically increased a glycosylated form of PD-L1 in their study. Exogenous FGF also increased glycosyltransferases, which may help keep PD-L1 on the surface of HNSCC cells. Their work suggests that the FGF/FGFR pathway may help cancer cells escape the immune system. This supports looking into new combination treatments that might help patients respond better to PD-1/PD-L1 axis reduction in HNSCC.

Source: sciencedirect.com/science/article/abs/pii/S1368837523002580